Introduction: Genetic Hepatobiliary Disease

Abbreviations

ACP

acylcarnitine profile

ADEK

vitamins A,D,E and K

AFP

alpha‐fetoprotein

ALT

alanine aminotransferase

ARPKD

autosomal recessive polycystic kidney disease

AST

aspartate aminotransferase

CK

creatinine kinase

ETC

electron transport chain

GAG

glycosaminoglycan

GALT

galactose‐1‐phosphate uridylyltransferase

GDF15

growth differentiation factor 15

HDL

high‐density lipoprotein

IV

intravenous

LCHAD

long‐chain L‐3 hydroxyacyl‐CoA dehydrogenase deficiency

LDH

lactate dehydrogenase

LDL

low‐density lipoprotein

L/P

lactate/pyruvate

MCT

medium chain triglycerides

MPS

mucopolysaccharidosis

MPSI

mucopolysaccharidosis type I

mtDNA

mitochondrial DNA

NAGS

N‐Acetylglutamate synthase

4‐OH

4‐hydroxy

PAA

plasma amino acids

PAS

periodic acid–Schiff

Rx

prescription/treatment

TCA

tricarboxylic acid cycle

TFP

trifunctional protein

TG

triglyceride

UAA

urine amino acids

UOA

urine organic acids

Hepatobiliary disease, defined as synthetic liver dysfunction, steatosis, cholestasis, hepatic fibrosis, or congenital biliary tree malformation, is a source of significant morbidity and mortality in the pediatric and adult populations and is the leading cause of liver transplantation. Hepatobiliary disease can be caused by infectious, autoimmune, and vascular etiologies, or can have an underlying genetic cause. Genetic liver disease presents most often during infancy but can also be juvenile or adult onset (Fig. 1). General disease categories include inherited metabolic liver disease, caused by deficiencies in metabolic pathways housed in the liver, and genetic/developmental liver disease, caused by defects in genes critical for hepatobiliary formation and function (Table 1).

FIG 1.

Select genetic liver diseases and their typical ages of onset.

TABLE 1.

Common Metabolic and Genetic Liver Diseases

Metabolic Liver Disease

Disorders of energy generation

Fatty acid oxidation defects

Glycogen storage disorders

Mitochondrial disease

Disorders of protein and amino acid metabolism

Citrin deficiency

Lysinuric protein intolerance

Tyrosinemia

Urea cycle disorders

Disorders of carbohydrate metabolism and modification

Congenital disorders of glycosylation

Galactosemia

Hereditary fructose intolerance

Disorders of lipoprotein metabolism

Abetalipoproteinemia

Lysosomal acid lipase deficiency

Lysosomal storage disorders

Gaucher disease

Mucopolysaccharidosis

Niemann‐Pick C disease

Pompe disease

Peroxisomal disorders

Zellweger spectrum disorder

Disorders of metal and porphyrin metabolism

Hereditary hemochromatosis

Porphyria

Wilson disease

Disorders of bile acid metabolism

Crigler‐Najjar syndrome

Progressive familial intrahepatic cholestasis

Genetic Liver Disease

Ciliopathy syndrome

Alstrom syndrome

Autosomal recessive polycystic kidney disease

Caroli disease/Caroli syndrome

Joubert syndrome

Morphogen and transcription factor defects

Alagille syndrome

Hardikar syndrome

HNF1B spectrum disease

Martinez‐Frias syndrome

Disorders of protein trafficking

Alpha‐1‐antitrypsin deficiency

Polycystic liver disease

Disorders of RNA metabolism

Trichohepatoenteric syndrome

Miscellaneous disorders

Aagenaes syndrome

Cystic fibrosis

Turner syndrome

Genetic liver disease can present predominantly as isolated hepatomegaly, steatosis, hepatitis, synthetic liver dysfunction, cholestasis, fibrosis, or as a mixed picture, complicating diagnosis (Fig. 2). General evaluation begins with measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma‐glutamyl transferase, total and direct bilirubin, albumin, prothrombin time, and partial thromboplastin time, which indicate the degree of hepatitis, cholestasis, and liver dysfunction. Creatinine kinase (CK) level should also be measured, because ALT and AST are highly expressed in muscle and their elevation may reflect a combination of muscle and liver disease or, in some cases, isolated muscle disease.

FIG 2.

Select genetic liver diseases and their dominant liver presentations.

Once the diagnosis of liver disease is established, liver ultrasound with Doppler studies can refine the differential by identifying hepatomegaly, steatosis, fibrosis/cirrhosis, portal hypertension, and macroscopic biliary tree abnormalities. Abnormal biliary structure is seen most commonly in biliary atresia, which is a pathophysiologically poorly understood, multifactorial disease and not a clearly genetic syndrome. Biliary dysgenesis without biliary atresia is suggestive of underlying genetic/developmental liver disease, such as Alagille syndrome, Hardikar syndrome, Martinez‐Frias syndrome, and ciliopathy spectrum disease (Fig. 3; Table 2). Developmental abnormalities, such as ductal plate malformation and microscopic biliary dysgenesis, are pathognomonic for underlying ciliopathy syndrome and require biopsy for diagnosis.

FIG 3.

Differential of cholestatic genetic liver diseases and their associated features.

TABLE 2.

General Features and Summaries of Select Genetic Liver Diseases

Genetic Liver Disease	Clinical Presentation
Ciliopathy Syndrome
Alstrom syndrome	Steatosis, episodic cardiomyopathy, hearing and visual impairment
ARPKD	Nephromegaly, kidney cysts, kidney failure, cholestasis, fibrosis, portal hypertension
Caroli disease/Caroli syndrome	Biliary dysgenesis +/− fibrosis and portal hypertension
Joubert syndrome	Developmental delay, hypotonia, molar tooth sign, kidney disease, cholestasis, portal hypertension, liver fibrosis
Morphogen and Transcription Factor Defects
Alagille syndrome	Cholestasis, liver fibrosis, right‐sided heart lesions, vertebral differences, posterior embryotoxon
Hardikar syndrome	Cleft lip/palate, aortic coarctation, pigmentary retinopathy, intestinal malrotation, urinary tract dilation, biliary dysgenesis, cirrhosis
HNF1B spectrum disease	Mild cholestasis, hepatitis, structural kidney differences, kidney cysts, diabetes, autism, intellectual disability
Martinez‐Frias syndrome	Extrahepatic biliary obstruction, congenital diabetes, anemia, duodenal atresia, pancreatic hypoplasia, growth failure
Disorders of Protein Trafficking
Alpha‐1‐antitrypsin deficiency	Cirrhosis, neonatal cholestasis, emphysema
Polycystic liver disease	Biliary tree cysts, hepatomegaly, abdominal pain
Disorders of RNA Metabolism
Trichohepatoenteric syndrome	Congenital diarrhea, abnormal hair, immunodeficiency, hepatitis
Miscellaneous Disorders
Aagenaes syndrome	Cholestasis, fibrosis, liver failure, lymphedema
Cystic fibrosis	Cholestasis, fibrosis, hepatitis, pancreatic insufficiency, recurrent sinopulmonary infections, bronchiectasis
Turner syndrome	Cystic hygroma/webbed neck, aortic coarctation, hyperinsulinism, structural kidney differences, premature ovarian failure, steatosis, liver vascular anomalies, liver fibrosis

Ultrasound findings of steatosis, hepatomegaly, and fibrosis often reflect underlying inherited metabolic disease. Accompanying acidosis and hypoglycemia are particularly concerning for these diagnoses. Screening tests for inborn errors of metabolism include acylcarnitine profile, urine organic acids, plasma amino acids, and urine amino acids, which identify accumulated metabolic intermediates and their carnitine and glycine conjugates, enabling inference of the location of the metabolic block. These tests can effectively diagnose fatty acid oxidation disorders, urea cycle disorders, mitochondrial disease, lysinuric protein intolerance, tyrosinemia, and hereditary fructose intolerance (Table 2). Importantly, because most metabolic pathways are housed within the liver, liver disease of any kind can produce metabolic derangements nonspecifically. Commonly seen abnormalities include elevated tyrosine, methionine, and phenylalanine on plasma amino acid testing; elevated 4‐hydroxyphenylpyruvate and 4‐hydroxyphenyllactate on urine organic acids; and elevated C16DC and C18DC species on acylcarnitine profile. Abnormalities can be seen in some of the more specialized biochemical laboratories as well. Biochemical disease markers can normalize and are not universally present, especially in mitochondrial disease, so normal biochemical laboratories do not exclude a particular diagnosis if there is a high index of clinical suspicion.

Measuring ammonia is important for immediate management decisions and also for diagnosis of urea cycle disorders, citrin deficiency, lysinuric protein intolerance, and certain mitochondrial diseases. Lactate, pyruvate, and growth differentiation factor 15 (GDF15) levels are elevated in mitochondrial diseases. GDF15 can be nonspecifically elevated in the neonatal period and because of cardiac and kidney disease. Other useful tests include a lipid profile, because dyslipidemia is seen in disorders of lipoprotein metabolism, Niemann‐Pick type C disease, glycogen storage disorders, citrin deficiency, and mitochondrial disease (Table 3). Carbohydrate‐deficient transferrin and N‐glycan testing facilitate diagnosis of congenital disorders of glycosylation and hereditary fructose intolerance. Polyol testing can establish a diagnosis of transaldolase deficiency.

TABLE 3.

Common Clinical Presentations and Diagnostic Laboratories for Select Metabolic Liver Diseases

Metabolic Liver Disease	Clinical Presentation	Diagnosis
Disorders of Energy Generation
Fatty acid oxidation defects	Hypoketotic hypoglycemia, rhabdomyolysis, cardiomyopathy, hepatomegaly, peripheral neuropathy (LCHAD and TFP), variable presentations common	ACP: ↑ of diagnostic acyl species
		UOA: ↑ of diagnostic dicarboxylic acid and acylglycine species
Glycogen storage disorders	Hypoglycemia, cardiomyopathy, hepatomegaly, muscle disease, neutropenia, malabsorption, cirrhosis, variable presentations common	Hypoglycemia, ↑ TGs, LDH, and uric acid in some
		Biopsy: positive PAS staining
Mitochondrial disease	Hypoglycemia, acidosis, lacticemia, cardiomyopathy, arrhythmia, progressive external ophthalmoplegia, endocrinopathy, rhabdomyolysis, kidney disease, pancreatic insufficiency, variable presentations common	PAA: ↑ alanine
		UOA: ↑ TCA intermediates and 3‐methylglutaconic acid
		L/P: ↑ lactate, n‐↑ pyruvate, ↑ L:P ratio
		Biopsy: abnormal mitochondria number, size and shape, abnormal cristae, matrix vacuoles
		Special tests: ETC activity, mtDNA content, GDF15
Disorders of Protein and Amino Acids Metabolism
Citrin deficiency	Cholestasis, hepatomegaly, steatosis, liver failure, episodic psychosis, episodic hyperammonemia, carbohydrate aversion, dyslipidemia	PAA: ↑ citrulline, threonine, methionine, ammonia: elevated
		Special tests: ↑ galactose and galactitol
Lysinuric protein intolerance	Protein aversion, vomiting, diarrhea and failure to thrive, hepatosplenomegaly, hyperammonemia, hypotonia, interstitial lung disease, glomerular disease, hemophagocytic lymphohistiocytosis	PAA: ↓ arginine, lysine, and ornithine
		UAA: ↑ arginine, lysine, and ornithine
Tyrosinemia	Liver failure, renal Fanconi, rickets, altered mental status, developmental delay (type I), corneal lesions, extremity hyperkeratosis (type II)	PAA: ↑ tyrosine, methionine
		UOA: ↑ succinylacetone and 4‐OH phenylpyruvate, lactate and acetate (type I), low 4‐OH phenylpyruvate in type II
		Special tests: succinylacetone, ↑ delta‐aminolevulinic acid (type I)
Urea cycle disorders	Episodic hyperammonemia, encephalopathy, hepatitis, fibrosis, developmental delay, protein aversion	PAA: ↑ glutamine, disease‐specific changes in arginine, citrulline, ornithine, and argininosuccinic acid
		UOA: ↑ orotic acid, uracil (some)
		Special tests: orotic acid
Disorders of Carbohydrate Metabolism and Modification
Congenital disorders of glycosylation	Hyperinsulinism, liver failure, abnormal fat pad distribution, immunodeficiency, cholestasis, liver failure, protein‐losing enteropathy, variable presentations common	Special tests: carbohydrate‐deficient transferrin, N‐glycan
Galactosemia	Liver failure, hyperbilirubinemia, Escherichia coli sepsis, speech delay, cataracts, kidney disease, growth delay, premature ovarian failure	Special tests: galactitol, galactose, galactose‐1‐phosphate, GALT activity, urine‐reducing substances
Hereditary fructose intolerance	Hypoglycemia, lactic acidosis and vomiting with fructose ingestion, growth failure, lethargy, seizures, hepatomegaly, liver failure, kidney failure	General labs: ↓ phosphate and magnesium, ↑ uric acid
		Special tests: carbohydrate‐deficient transferrin, urine‐reducing substances
Transaldolase deficiency	Liver failure, coagulopathy, anemia, thrombocytopenia, hepatosplenomegaly, cirrhosis, cutis laxa, dysmorphic features, hypertrichosis	Special tests: urine polyols by mass spectrometry
Disorders of Lipoprotein Metabolism
Abetalipoproteinemia	Steatosis, ataxia, dysarthria, proprioception loss, retinitis pigmentosa, anemia	Lipid panel: ↓↓↓ LDL, ↓↓ TGs
		Special tests: acanthocytes on blood smear
Lysosomal acid lipase deficiency	Hepatosplenomegaly, adrenal insufficiency, malabsorption, failure to thrive, portal hypertension, cirrhosis, dyslipidemia (neonatal form), dyslipidemia, hepatosplenomegaly, portal hypertension, atherosclerotic cardiovascular disease (attenuated)	Lipid panel: ↑ LDL, ↑ TGs, ↓↓ HDL
		Biopsy: steatosis, lipid‐filled cytoplasmic vesicles, lipid‐filled lysosomes
		Special tests: lysosomal acid lipase enzyme activity, oxysterols
Lysosomal Storage Disorders
Gaucher disease	Hepatosplenomegaly, anemia, thrombocytopenia, lytic bone lesions, neurological disease (types 2 and 3), ichthyosis (neonatal lethal)	Biopsy: steatosis, lipid‐loaded macrophages (Gaucher cells)
		Special tests: glucocerebrosidase enzyme testing, chitotriosidase levels
Mucopolysaccharidoses	Hepatosplenomegaly, corneal clouding, cardiomyopathy, bone disease, developmental delay	Biopsy: membrane‐bound inclusions (GAG‐filled lysosomes)
		Special tests: urine glycosaminoglycans, enzyme testing
Niemann‐Pick type C disease	Hepatosplenomegaly, cholestasis, pulmonary disease, neurodegeneration, ataxia, seizures, psychosis	Biopsy: vacuolated cells, lysosomal lipid accumulation
		Special tests: oxysterols, fibroblast filipin staining
Pompe disease	Hypotonia, hepatomegaly, elevated aminotransferases, cardiomyopathy (infantile)	Biopsy: glycogen‐filled vacuoles, positive PAS staining
		Special tests: alpha‐glucosidase activity, urine hex4
Peroxisomal Disorders
Zellweger syndrome	Hepatomegaly, cholestasis, liver dysfunction, kidney disease, hypotonia, respiratory failure, adrenal insufficiency, seizures, bone stippling, hearing and vision loss	Biopsy: absent/abnormal peroxisomes, trilamellar inclusions
		Special tests: ↑ very long‐chain fatty acids, ↓ plasmalogens
Disorders of Metal and Porphyrin Metabolism
Hereditary hemochromatosis	Elevated aminotransferases, liver failure, cirrhosis, diabetes, hypogonadism, cardiomyopathy	Special tests: ↑ transferrin saturation and ferritin
Porphyria	Elevated aminotransferases, liver fibrosis, hepatocellular carcinoma, photosensitivity, pain crises, altered mental status	Special tests: urine, stool, and serum porphyrins
Wilson disease	Episodic jaundice and hepatitis, liver failure, movement disorder, psychosis, Kayser‐Fleischer rings; variable presentations common: pediatric presentation is typically isolated liver disease	Special tests: ↑ copper, ↓ ceruloplasmin
Disorders of Bile Acid Metabolism
Crigler‐Najjar syndrome	Recurrent unconjugated hyperbilirubinemia, kernicterus, encephalopathy, movement disorder, hearing loss, developmental delay	↑↑ Unconjugated bilirubin
Progressive familial intrahepatic cholestasis 1/2/3	Cholestasis, cirrhosis, hepatocellular carcinoma, pruritis	Special tests: urine bile acid analysis

Many inherited liver diseases that present with steatosis, including disorders of lipoprotein metabolism, lysosomal acid lipase deficiency, Niemann‐Pick type C disease, and Wilson disease, require more specialized biochemical testing (Table 3; Fig. 4). Many inherited metabolic liver diseases also present with isolated hepatomegaly or elevated aminotransferases with or without hepatomegaly and also require specialized testing, including disorders of glycogen metabolism, peroxisomal metabolism, and lysosomal storage disorders (Table 3; Fig. 5). Lysosomal storage disorders are diagnosed through enzyme activity testing and measurement of accumulating metabolites. Peroxisomal disorders are diagnosed through measurement of the very long‐chain fatty acids and plasmalogens. Glycogen storage disorders can be diagnosed by liver biopsy by visualizing glycogen accumulation with periodic acid–Schiff (PAS) staining. Liver biopsy with electron microscopy can facilitate the diagnosis of numerous metabolic diseases by identifying infiltrating cells, abnormal organelle morphology, the presence of storage material, and lipid accumulation (Table 3). Liver tissue enables enzymology assays to be performed for enzymes expressed only in liver. Electron transport chain activity assays and mitochondrial DNA (mtDNA) abundance testing can also be performed on biopsy tissue and can help to clarify a mitochondrial diagnosis.

FIG 4.

Differential of genetic liver diseases that present with steatosis and their associated features.

FIG 5.

Differential of genetic liver diseases that present with elevated aminotransferases and their associated features.

Many inherited metabolic liver diseases and most of the genetic/developmental liver diseases cannot be entirely diagnosed through biochemical testing or liver biopsy because of disease variability, lack of biochemical marker, or poor sensitivity of the biochemical marker, necessitating genetic testing for definitive diagnosis. Common genetic testing modalities for liver disease include single‐gene sequencing and deletion/duplication studies when the likely causal gene is known; gene panel testing, which sequences a group of genes known to be associated with a particular liver trait, such as cholestasis or liver failure; exome sequencing, which interrogates all genes in the human genome simultaneously; and mtDNA sequencing, which sequences the mitochondrial genome. Chromosomal microarray, which detects larger copy number variations, also can be diagnostic if the causal genetic change is a large deletion or duplication. Definitive diagnosis is paramount for early initiation of appropriate treatment, especially in the cases of inherited metabolic liver disease (Table 4).

TABLE 4.

Treatments and Surveillance for Select Metabolic Liver Diseases

Disease	Treatment and Monitoring
Disorders of Energy Generation
Fatty acid oxidation defects	Rx: avoidance of fasting, hospitalization during periods of illness and before procedures for IV dextrose, cornstarch before bed, avoidance of salicylates, carnitine supplementation; low‐fat diet, MCT oil supplementation for long‐chain disorders
	Surveillance: CK, echocardiogram, liver function (long‐chain disorders)
Glycogen storage disorders	Rx: disorder specific; avoidance of fasting, continuous or frequent high‐starch feeds, sugar restriction, high‐protein diet and MCT oil, liver transplant
	Surveillance: liver ultrasound and AFP (liver adenoma, malignancy) screening for osteoporosis and kidney disease
Mitochondrial disease	Rx: vitamin cocktails, arginine supplementation, N‐acetylcysteine (some)
	Surveillance: echocardiogram, electrocardiogram, ophthalmology examination, kidney function, endocrinopathies, stroke, pancreatic insufficiency, diabetes, developmental delay, liver dysfunction/cholestasis
Disorders of Protein and Amino Acid Metabolism
Citrin deficiency	Rx: galactose‐free diet, protein/fat‐rich diet, nitrogen scavengers, sodium pyruvate supplementation, MCT oil, arginine supplementation, liver transplantation
	Surveillance: vitamin D and zinc levels, liver function studies and imaging for steatosis, cholestasis, and fibrosis
Lysinuric protein intolerance	Rx: protein restriction, nitrogen scavengers, lysine and citrulline supplementation, carnitine supplementation
	Surveillance: interstitial lung disease, kidney disease, immunodeficiency, portal hypertension, liver dysfunction, bone health
Tyrosinemia	Rx: nitisinone (tyrosinemia type I), tyrosine and phenylalanine‐restricted diet
	Surveillance: ophthalmology examination (corneal lesions), liver function, liver fibrosis, screening for renal Fanconi, screening for learning delays
Urea cycle disorders	Rx: low‐protein diet, supplementation of urea cycle intermediates (diagnosis‐dependent, citrulline, arginine), nitrogen scavengers, carglumic acid (NAGS deficiency), liver transplantation
	Surveillance: growth, blood pressure, hepatic fibrosis, hepatocellular carcinoma
Disorders of Carbohydrate Metabolism and Modification
Galactosemia	Rx: galactose‐free diet, vitamin D supplementation
	Surveillance: growth, vitamin deficiencies, cataracts, premature ovarian failure, speech delay
Hereditary fructose intolerance	Rx: fructose, sucrose and sorbitol‐free diet, vitamin supplementation
	Surveillance: monitoring of growth, liver and kidney function
Congenital disorders of glycosylation	Rx: mannose and galactose supplementation (disease specific)
	Surveillance: hypoglycemia, endocrinopathies, growth, development, liver function
Transaldolase deficiency	Rx: supportive, N‐acetylcysteine
	Surveillance: monitoring for endocrinopathy, renal Fanconi, and rickets; liver ultrasound and AFP (malignancy)
Disorders of Lipoprotein Metabolism
Abetalipoproteinemia	Rx: low‐fat diet, essential fatty acid supplementation, ADEK vitamin supplementation
	Surveillance: growth, anemia, ataxia/neurological disease, retinitis pigmentosa, liver function tests, lipid profile
Lysosomal acid lipase deficiency	Rx: enzyme replacement therapy, lipid‐lowering medications, low‐fat diet
	Surveillance: growth, vitamin deficiencies, adrenal insufficiency (neonatal disease), dyslipidemia, liver function, cirrhosis/portal hypertension
Lysosomal Storage Disorders
Gaucher disease	Rx: enzyme replacement therapy, splenectomy (if needed), substrate reduction therapy (miglustat)
	Surveillance: bone health, vitamin deficiencies, cytopenias, pulmonary hypertension
Mucopolysaccharidosis	Rx: enzyme replacement therapy (MPS I, II, IVA, V, VI, VII), bone marrow transplantation (MPSI)
	Surveillance: hearing loss, cardiomegaly/cardiomyopathy, obstructive sleep apnea, pulmonary hypertension, airway impingement, spinal cord compression, corneal clouding, bone pain/disease, retinal disease, learning differences
Niemann‐Pick type C disease	Rx: supportive, miglustat (not US)
	Surveillance: developmental delays, seizures, abnormal eye movements, cholestasis, liver dysfunction
Pompe disease	Rx: enzyme replacement
	Surveillance: echocardiogram, CK, hepatomegaly, hearing loss, obstructive sleep apnea, developmental delay
Peroxisomal Disorders
Zellweger spectrum disease	Rx: supportive
	Surveillance: liver dysfunction, portal hypertension, adrenal insufficiency, respiratory compromise, cataracts, kidney stones, seizures
Disorders of Metal Metabolism
Hereditary hemochromatosis	Rx: phlebotomy
	Surveillance: iron overload, cardiomyopathy, arrhythmia, hypogonadism, diabetes, cirrhosis, hepatocellular carcinoma
Porphyrias	Rx: avoiding triggers (alcohol, medications), early treatment of infections, sun avoidance, hydroxychloroquine, therapeutic phlebotomy, hospitalization for acute crises, heme arginate
	Surveillance: dermatology examinations, monitoring for cirrhosis and hepatocellular carcinoma
Wilson disease	Rx: copper chelation, zinc supplementation
	Surveillance: psychiatric disease, movement disorder, hepatitis, liver failure
Disorders of Bile Acid Metabolism
Crigler‐Najjar syndrome	Rx: phototherapy, exchange transfusion, heme oxygenase inhibitors, liver transplant
	Surveillance: bilirubin levels
Progressive familial intrahepatic cholestasis	Rx: supportive care, ursodeoxycholic acid, liver transplant
	Surveillance: liver fibrosis, cholestasis, liver failure, portal hypertension

Importantly, although genetic testing technology has immensely improved in the past 10 years, providers are unable to secure a genetic diagnosis in a significant portion of individuals with suspected underlying genetic liver disease. This is related to our incomplete understanding of all genes involved in liver disease and also because of intronic and regulatory variants that are not detected by conventional testing modalities. Whole‐genome sequencing and RNA sequencing are emerging technologies to address these shortcomings; however, a current technology that can be harnessed for diagnostics is liver biopsy.

In this special issue of Clinical Liver Disease, we highlight a number of common genetic and metabolic liver diseases, including mitochondrial hepatopathy, ciliopathy syndromes, congenital disorders of glycosylation, inborn errors of lipoprotein metabolism, alpha‐1‐antitrypsin deficiency, disorders of bile acid metabolism, and urea cycle disorders and highlight their liver‐based physiology (Figure 6). We review the clinical presentations, diagnostics, and treatment modalities for these conditions with emphasis on emerging therapies and new considerations now that individuals with genetic liver diseases are surviving into adulthood.

FIG 6.

Overview of metabolic pathways housed in the liver. Left Lower: The biliary tree is an interconnected series of tubules in the liver that helps transport bile and other toxins out of the liver. The ducts are lined by ciliated epithelium, which facilitate bile duct growth and patterning in response to external stimuli. Ciliary dysfunction is associated with ciliopathy‐spectrum disease. The bile duct are also lined with multiple channels that modulate bile composition. Channel deficiencies are associated with many conditions, including Cystic Fibrosis and progressive familial intrahepatic cholestasis. Left Upper: The endoplasmic reticulum and Golgi apparatus are sites of protein glycosylation, lipoprotein biosynthesis, and alpha‐1 antitrypsin synthesis. Bile acid and cholesterol biosynthesis take place in the endoplasmic reticulum and peroxisome. Middle: The electron transport chain is housed in the mitochondria. The urea cycle, fatty acid oxidation and porphyrin metabolism are caused in the cytosol and mitochondria. Polyol metabolism takes place in the cytosol. Lipoprotein catabolism, mucopolysaccharide metabolism, some glycogen metabolism, and some glycolipid metabolism takes place in the lysosome. Disruption of any of these pathways housed in the liver can cause liver disease. Abbreviations: B: Apolipoprotein B; CFTR: Cystic fibrosis transmembrane conductance regulator; FC: Free cholesterol; LAL: Lysosomal acid lipase; MPS: Mucopolysaccharide; MTP: Microsomal triglyceride transfer protein; NPC: Niemann‐Pick disease C; PFIC: Progressive familial intrahepatic cholestasis; TGs: Triglyceride